Behavioral sensitivity to alcohol can be modified as a function of both environmental and genetic factors. The underlying basis of this effect is the ability of neurons to adapt in response to environmental perturbations including, but not limited to alcohol exposure, and the specific nature of this response is dependent on genetic makeup. These processes may be an important feature in the etiology of alcoholism. Evidence indicates that drugs acting on dopamine (DA) neurons are able to alter the behavioral response to alcohol in rodents. Thus, 24 hrs after a single treatment with the DA antagonist haloperidol or the indirect DA agonist methamphetamine, rats become more or less sensitive to alcohol, respectively, and "rapid" tolerance develops one day after a single dose of alcohol. These acute drug responses will be exploited to investigate the global gene expression changes occurring in DA pathways that contribute to altered alcohol sensitivity. Specific Aim 1 will fully characterize the behavioral response to alcohol (loss of righting reflex) 24 hrs after acute treatment with haloperidol, alcohol, or methamphetamine in replicate inbred High and Low Alcohol Sensitive rat strains. Gene expression analyses will be performed in Specific Aim 2. Rats will be sacrificed at 8 hrs following administration of a single optimal dose of each drug and the striatum and ventral midbrain will be dissected. RNA will be extracted from these structures and gene expression will be determined with the use of the Affymetrix GeneChip system. This will provide a total of 16 experimental conditions comprised of different drug/genotype combinations. It is postulated that each of these conditions will show different, but overlapping gene expression profiles. The genes that are important in the altered alcohol response will be identified by clustering and discriminative analysis procedures in a comparison of the expression profiles and the behavioral responses among the 16 conditions. Specific Aim 3 will validate important gene expression changes with the use of ribonuclease protection assays and/or real-time quantitative PCR. The results of the proposed studies will offer insight into the neuroadaptive processes that contribute to alcohol abuse and will also provide more information from which to further investigate alcohol related neuroadaptation.